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The soluble guanylate cyclase activator BAY 58-2667 protects against morbidity and mortality in endotoxic shock by recoupling organ systems.

Vandendriessche B, Rogge E, Goossens V, Vandenabeele P, Stasch JP, Brouckaert P, Cauwels A - PLoS ONE (2013)

Bottom Line: Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality.In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues.In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

ABSTRACT
Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ failure (MOF). The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the regulation of (micro)vascular homeostasis, cardiac function and, consequently, organ function. However, it can become inactivated when exposed to reactive oxygen species (ROS). The resulting heme-free sGC can be reactivated by the heme- and nitric oxide (NO)-independent sGC activator BAY 58-2667 (Cinaciguat). We report that late (+8 h) post-treatment with BAY 58-2667 in a mouse model can protect against lethal endotoxic shock. Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality. In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues. Hemodynamic parameters (blood pressure and heart rate) were decreased, and linear and nonlinear indices of blood pressure variability, reflective for (un)coupling of the communication between the autonomic nervous system and the heart, were improved after late protective treatment with BAY 58-2667. In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality when given in the correct treatment window, which probably depends on the dynamics of the heme-free sGC pool, in turn influenced by oxidative stress. We speculate that, considering the central role of sGC signaling in many pathways required for maintenance of (micro)circulatory homeostasis, BAY 58-2667 supports organ function by recoupling inter-organ communication pathways.

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Effect of BAY 58-2667 and BAY 41-2272 treatment on hemodynamic parameters.Mean arterial pressure (MAP) and heart rate (HR) were recorded via implanted telemetry devices. (A–B) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 58-2667 (+3 h or +8 h) or vehicle control (+3 h or +8 h); 2 h pre- until 4 h post-treatment of data is shown (n = 4). (C–D) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 41-2272 (+3 h or +8 h, n = 2) or vehicle control (+3 h or +8 h, n = 1); 2 h pre- until 4 h post-treatment of data is shown. (E–F) Unchallenged mice were injected with saline (PBS), 100 µg/kg or 300 µg/kg BAY 58-2667; 4 h of data post-injection is shown (n = 4). Data are means and were compared to vehicle controls by fitting a linear mixed model (see Table S2 for fixed term statistics). ****, p≤0.0001; ***, p≤0.001; *, p≤0.05; ns = nonsignificant; trt = treatment effect and time×trt = time-treatment interaction.
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pone-0072155-g005: Effect of BAY 58-2667 and BAY 41-2272 treatment on hemodynamic parameters.Mean arterial pressure (MAP) and heart rate (HR) were recorded via implanted telemetry devices. (A–B) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 58-2667 (+3 h or +8 h) or vehicle control (+3 h or +8 h); 2 h pre- until 4 h post-treatment of data is shown (n = 4). (C–D) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 41-2272 (+3 h or +8 h, n = 2) or vehicle control (+3 h or +8 h, n = 1); 2 h pre- until 4 h post-treatment of data is shown. (E–F) Unchallenged mice were injected with saline (PBS), 100 µg/kg or 300 µg/kg BAY 58-2667; 4 h of data post-injection is shown (n = 4). Data are means and were compared to vehicle controls by fitting a linear mixed model (see Table S2 for fixed term statistics). ****, p≤0.0001; ***, p≤0.001; *, p≤0.05; ns = nonsignificant; trt = treatment effect and time×trt = time-treatment interaction.

Mentions: Figure 5 shows hemodynamic parameters from mice that were treated with vehicle, BAY 41-2272 or BAY 58-2667, +3 h or +8 h after challenge with LPS (Fig. 5, A–D), as well as from healthy mice (Fig. 5, E–F). For LPS-challenged mice, a time window of 2 h pre- until 4 h post-treatment was analyzed. Injection of saline in healthy mice typically prompted a transient (±30 min) stress-induced increase in mean arterial pressure (MAP), while injection of BAY 58-2667 (100 µg/kg or 300 µg/kg) caused a dose-dependent drop in MAP that lasted for 15–25 min (Fig. 5, E). Shortly after the drop in MAP, a prolonged compensatory increase in HR was observed (Fig. 5, F). A phase I dose escalating study in healthy human volunteers showed that BAY 58-2667 caused a rapid decrease in systemic vascular resistance (SVR), followed by a reduction of MAP that, in turn, was followed by a compensatory increase in HR and stroke volume (SV) [27]. Thus, activation of the small pool of heme-free sGC present at baseline can have systemic effects, albeit limited. Our data in non-challenged (healthy) mice confirmed this.


The soluble guanylate cyclase activator BAY 58-2667 protects against morbidity and mortality in endotoxic shock by recoupling organ systems.

Vandendriessche B, Rogge E, Goossens V, Vandenabeele P, Stasch JP, Brouckaert P, Cauwels A - PLoS ONE (2013)

Effect of BAY 58-2667 and BAY 41-2272 treatment on hemodynamic parameters.Mean arterial pressure (MAP) and heart rate (HR) were recorded via implanted telemetry devices. (A–B) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 58-2667 (+3 h or +8 h) or vehicle control (+3 h or +8 h); 2 h pre- until 4 h post-treatment of data is shown (n = 4). (C–D) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 41-2272 (+3 h or +8 h, n = 2) or vehicle control (+3 h or +8 h, n = 1); 2 h pre- until 4 h post-treatment of data is shown. (E–F) Unchallenged mice were injected with saline (PBS), 100 µg/kg or 300 µg/kg BAY 58-2667; 4 h of data post-injection is shown (n = 4). Data are means and were compared to vehicle controls by fitting a linear mixed model (see Table S2 for fixed term statistics). ****, p≤0.0001; ***, p≤0.001; *, p≤0.05; ns = nonsignificant; trt = treatment effect and time×trt = time-treatment interaction.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756074&req=5

pone-0072155-g005: Effect of BAY 58-2667 and BAY 41-2272 treatment on hemodynamic parameters.Mean arterial pressure (MAP) and heart rate (HR) were recorded via implanted telemetry devices. (A–B) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 58-2667 (+3 h or +8 h) or vehicle control (+3 h or +8 h); 2 h pre- until 4 h post-treatment of data is shown (n = 4). (C–D) Mice were injected i.v. with 9.5–11 mg/kg LPS (E. coli), and treated i.v. with 100 µg/kg BAY 41-2272 (+3 h or +8 h, n = 2) or vehicle control (+3 h or +8 h, n = 1); 2 h pre- until 4 h post-treatment of data is shown. (E–F) Unchallenged mice were injected with saline (PBS), 100 µg/kg or 300 µg/kg BAY 58-2667; 4 h of data post-injection is shown (n = 4). Data are means and were compared to vehicle controls by fitting a linear mixed model (see Table S2 for fixed term statistics). ****, p≤0.0001; ***, p≤0.001; *, p≤0.05; ns = nonsignificant; trt = treatment effect and time×trt = time-treatment interaction.
Mentions: Figure 5 shows hemodynamic parameters from mice that were treated with vehicle, BAY 41-2272 or BAY 58-2667, +3 h or +8 h after challenge with LPS (Fig. 5, A–D), as well as from healthy mice (Fig. 5, E–F). For LPS-challenged mice, a time window of 2 h pre- until 4 h post-treatment was analyzed. Injection of saline in healthy mice typically prompted a transient (±30 min) stress-induced increase in mean arterial pressure (MAP), while injection of BAY 58-2667 (100 µg/kg or 300 µg/kg) caused a dose-dependent drop in MAP that lasted for 15–25 min (Fig. 5, E). Shortly after the drop in MAP, a prolonged compensatory increase in HR was observed (Fig. 5, F). A phase I dose escalating study in healthy human volunteers showed that BAY 58-2667 caused a rapid decrease in systemic vascular resistance (SVR), followed by a reduction of MAP that, in turn, was followed by a compensatory increase in HR and stroke volume (SV) [27]. Thus, activation of the small pool of heme-free sGC present at baseline can have systemic effects, albeit limited. Our data in non-challenged (healthy) mice confirmed this.

Bottom Line: Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality.In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues.In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

ABSTRACT
Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ failure (MOF). The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the regulation of (micro)vascular homeostasis, cardiac function and, consequently, organ function. However, it can become inactivated when exposed to reactive oxygen species (ROS). The resulting heme-free sGC can be reactivated by the heme- and nitric oxide (NO)-independent sGC activator BAY 58-2667 (Cinaciguat). We report that late (+8 h) post-treatment with BAY 58-2667 in a mouse model can protect against lethal endotoxic shock. Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality. In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues. Hemodynamic parameters (blood pressure and heart rate) were decreased, and linear and nonlinear indices of blood pressure variability, reflective for (un)coupling of the communication between the autonomic nervous system and the heart, were improved after late protective treatment with BAY 58-2667. In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality when given in the correct treatment window, which probably depends on the dynamics of the heme-free sGC pool, in turn influenced by oxidative stress. We speculate that, considering the central role of sGC signaling in many pathways required for maintenance of (micro)circulatory homeostasis, BAY 58-2667 supports organ function by recoupling inter-organ communication pathways.

Show MeSH
Related in: MedlinePlus